Mems device and method for delivery of therapeutic agents

ABSTRACT

Embodiments of an implantable device for delivering a therapeutic agent to a patient include a reservoir configured to contain a liquid comprising the therapeutic agent, and a cannula in fluid communication with the reservoir. The cannula is shaped to facilitate insertion thereof into a patient&#39;s eyeball.

CLAIM OF PRIORITY

This application is a continuation of, claims priority to and thebenefit of, and incorporates by reference herein in its entirety U.S.patent application Ser. No. 11/686,310, which was filed on Mar. 14, 2007and which claimed priority to and the benefit of U.S. Provisional PatentApplication No. 60/781,969, filed Mar. 14, 2006, entitled “ProvisionalPatent Report: Implantable MEMS Ocular Drug Delivery System,” which isalso incorporated in its entirety by reference herein.

STATEMENT REGARDING FEDERALLY SPONSORED R&D

Work leading to the invention described herein was supported by the U.S.Government, so the U.S. Government has certain rights to the inventionpursuant to Grant No. EEC-0310723 awarded by the National ScienceFoundation.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This application relates generally to devices and methods for deliveryof therapeutic agents to a patient, and more specifically to delivery oftherapeutic agents by an implanted device.

2. Description of the Related Art

Medical treatment often requires administration of a therapeutic agent(e.g., medicament, drugs; to a particular part of the body, intravenousinjection has long been a mainstay in medical practice to deliver drugssystemically. Some maladies, however, requires administration of dragsto anatomical regions or portions to which access is more difficult toachieve.

Eyes are a prime example of anatomical regions in which access isconstrained. Ocular pathologies such as diabetic retinopathy and maculardegeneration are best treated by administration of drugs to the vitreoushumor, which has no fluid communication with the vasculature. Suchadministration not only delivers drug directly to where it is needed,but also importantly minimizes the exposure of fee rest of the body tothe drug and therefore to its inevitable side effects.

Injection into the patient's body (e.g., into the vitreous humor of theeye), white medically feasible, delivers a bolus of drag. Many times,however, administration of a bolus of drug is undesirable. For example,drugs often have concentration-dependent side effects that limit themaximum concentration optimally administered to the body. Certain dragsexert their therapeutic action only when their concentration exceeds athreshold value for a given period. For such drugs, the exponentialdecay in concentration with time of a bolus injection would necessitaterepeated injections to maintain the desired drug concentration in feebody. Repeated injections not only entail the expense and inconvenienceof repeated office visits, but also the unpleasantness of the injectionsthemselves. In addition, with regard to intraocular treatments, repeatedinjections increase the risk of damage to the eye through infection,hemorrhage, or retinal detachment.

These problems are particularly severe in the case of chronic ailmentsthat require long-term administration of a drug either for treatmentand/or for prophylactic maintenance. Other chronic diseases, such asdiabetes, are now treated by devices that gradually deliver therapeuticmedicaments over time, avoiding or at least reducing the “sawtooth”pattern associated with repeated administration of boluses.

SUMMARY OF THE INVENTION

In certain embodiments, an implantable device for delivering atherapeutic agent to a patient is provided. The device comprises areservoir configured to contain a liquid comprising the therapeuticagent. The device further comprises a cannula in fluid communicationwith the reservoir, the cannula having an outlet configured to be influid communication with the patient. The device further comprises avalve comprising a movable element movable between a first position anda second position. The movable element comprises an orificetherethrough, wherein the liquid flows through the orifice to the outletwhen the movable element is in the first position and wherein the liquiddoes not flow through the orifice to the outlet when the movable elementis in the second position.

In certain embodiments, an implantable device for delivering atherapeutic agent to a patient is provided. The device comprises areservoir configured to contain a liquid comprising the therapeuticagent. The device further comprises a cannula in fluid communicationwith the reservoir. The cannula has an outlet configured to be in fluidcommunication with the patient. The device further comprises a firstelectrode and a second electrode, at least one of the first electrodeand the second electrode is planar. The device further comprises amaterial in electrical communication with the first and secondelectrodes. A voltage applied between the first electrode and the secondelectrode produces gas from the material, the gas forcing the liquid toflow from the reservoir to the outlet.

In certain embodiments, a method of making an implantable device fordelivering a therapeutic agent to a patient is provided. The methodcomprises forming a plurality of structural layers. The method furthercomprises bonding the plurality of structural layers together to form areservoir configured to contain a liquid and a cannula in fluidcommunication with the reservoir, the cannula having an outletconfigured to be in fluid communication with the patient.

In certain embodiments, a method is provided for delivering atherapeutic agent to a patient. The method comprises providing a deviceimplanted in or on a patient. The device comprises a reservoircontaining a liquid comprising the therapeutic agent. The device furthercomprises a cannula in fluid communication with the reservoir, thecannula having an outlet in fluid communication with the patient. Thedevice further comprises a first electrode, a second electrode, and amaterial in electrical communication with the first and secondelectrodes. The method further comprises applying a first voltagebetween the first electrode and the second electrode to produce gas fromthe material, the gas forcing the liquid to flow from the reservoir tothe outlet. The method further comprises applying a second voltagebetween the first electrode and the second electrode to produce thematerial from the gas.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exploded view of the three layers that form an exampledrug delivery device compatible with certain embodiments describedherein.

FIG. 2 shows an assembled example drug delivery device compatible withcertain embodiments described herein.

FIG. 3 illustrates an example location for implantation of an exampledrug delivery device in the eye.

FIG. 4 shows optical microscope images of a cross-sectional view ofpolydimethylsiloxane after it was punctured using a (a) 20-gaugestandard needle, (b) 30-gauge non-coring needle, and (c) 30-gauge coringneedle.

FIG. 5 shows a cross-sectional view of the device depicted in FIG. 2.

FIGS. 6A and 6B show cross-sectional views of the operation of anexample valve compatible with certain embodiments described herein.

FIG. 7 is a photomicrograph of one embodiment of as assembled valvecompatible with certain embodiments described herein.

FIG. 8 is a series of photomicrographs illustrating the operation of anexample valve in accordance with certain embodiments described herein.

FIG. 9 shows an example of an assembled intraocular drug delivery devicecompatible with certain embodiments described herein.

FIG. 10 schematically illustrates an example device utilizingelectrolytic pumping in accordance with certain embodiments describedherein.

FIG. 11 shows the base layer of an example device showing integrateddrug delivery cannula and electrolysis electrodes.

FIGS. 12A and 12B show an example of the base layer next to a reservoircap and with an assembled reservoir, respectively, in accordance withcertain embodiments described herein.

FIGS. 13A and 13B schematically illustrate an example electrolysismicropump compatible with certain embodiments described herein.

FIGS. 14A and 14B schematically illustrate top and cut-away side viewsof an example electrolysis micropump compatible with certain embodimentsdescribed herein.

FIGS. 15A-15D show successive cut-away views of a drug reservoir andpump chamber compatible with certain embodiments described herein. FIG.15D includes a legend applicable to FIGS. 15A-15D.

FIGS. 16A-16I show various views of an example of a drug delivery systemwith drug reservoir, cannula, valving, pump, refillable port, and suturelabs.

FIG. 17 shows the internal structure of one type of injection port onthe reservoir compatible with certain embodiments described herein.

FIGS. 18A-18K show an example process flow for fabricating a siliconmask and making a molded polydimethylsiloxane (PDMS) layer with siliconshown with dark shading, parylene shown with no shading, and PDMS shownwith diagonal line shading.

FIGS. 19A-19M show an example process flow to fabricate the base layerof an implantable drug delivery device that includes electrodes forelectrolytic pumping and an integral cannula in accordance with certainembodiments described herein. FIG. 19M includes a legend applicable toFIGS. 19A-19M.

FIG. 20 illustrates ex vivo testing of the device in a porcine eyeshowing the electrolysis driven delivery of dyed DI water into theanterior chamber.

FIG. 21A illustrates current-controlled flow delivery after evaporationcompensation (mean±SE, n=4) with the calibrated water evaporation ratein the micro-pipette of about 30 nL/min for example devices implanted inenucleated porcine eyes; FIG. 21B illustrates low flow rate operation ofthe example devices of FIG. 21A; FIG. 21C illustrates pump efficiencycalculated from flow delivery data for the example devices of FIG. 21A;FIG. 21D illustrates typical gas recombination observed in the exampledevices of FIG. 21A. 50 microamp current was applied for 10 minutes andthen turned off.

FIG. 22 illustrates bolus delivery of 250 nL doses using current pulses.

FIG. 23 illustrates now performance under physiological back pressures(mean±SE, n=4).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Unless otherwise specified, technical terms are used herein to havetheir broadest meaning to persons skilled in the art, including but notlimited to, the meanings specified in the McGraw-Hill Dictionary ofScientific and Technical Terms, 6^(th) edition.

In vivo sustained release implants are a new and promising technology.Most utilize minimal surgery to be inserted. There is a trade-offbetween size and repeated use for these implants. Smaller devicesprovide comfort but contain a limited amount of drug, thus requiringreplacement. Larger devices do not need to be replaced but instead canbe refilled. Certain pharmaceutical treatments of chronic eye diseases(e.g., glaucoma) necessitate repeated doses to be delivered to the eye.Such devices are also advantageously small due to the space restrictionsof the eye. Therefore, in certain embodiments described herein, drugdelivery systems for the eye advantageously combine small size and arefillable reservoir.

Drug delivery devices for the eye have particularly demandingrequirements. Clearly, any such device is advantageously made as smallas possible to minimize the discomfort of its presence in the eye. Onthe other hand, the device advantageously holds as much drug aspossible, to maximize the time before the drug supply is exhausted andthe device must be replaced or refilled. These mutually antitheticalrequirements greatly complicate the challenge of designing practicalimplantable devices for delivering drugs within the eye. In addition,some applications, such as administering treatment within the eye, poseeven more serious problems. Repeated injections can easily damagedelicate ocular tissues, and can result in hemorrhage, infection, andcataracts. In addition, some areas of the body simply cannot be reachedby injection.

A need therefore exists for a device for drug delivery to a patient'sbody for which certain embodiments are small but can deliver asufficient amount of drug over an extended period without needing to bereplaced. Certain embodiments described herein answer this need byproviding an implantable drug delivery device that, while small, isrefillable, and therefore can supply a fluid, such as a solution of adrag, over extended periods by being refilled in situ rather thanreplaced. Certain embodiments described herein provide a device with areservoir that has a self-resealing upper layer feat can be pierced witha needle for refilling, and a lower layer that resists needle puncturesand thereby protects the eye from accidental injury during the refillingprocess.

Certain embodiments described herein provide an implantable intraoculardrag delivery system that includes a refillable reservoir, a cannula,and a valve. The refillable reservoir holds the fluid to be delivered,the cannula directs the fluid to the targeted site, and the valvecontrols when fluid is delivered and prevents backflow. The cannula ofcertain embodiments is tapered to facilitate its insertion into the eye.In general, the fluid will contain one or more drugs. The term “drug” isused herein to have its broadest meaning to persons skilled in the art,including, bra not limited to, drug substance per se, medicaments,therapeutic agents, and fluids containing such substances.

FIG. 1 and FIG. 2 schematically illustrate an exploded view and anassembled view, respectively, of an example device 5 compatible withcertain embodiments described herein. The device 5 comprises a reservoir100 configured to contain a liquid comprising a therapeutic agent. Thedevice 5 further comprises a cannula 110 in fluid communication with thereservoir 100. The cannula 110 has an outlet 115 configured to be influid communication with the patient. The device 5 further comprises avalve 120 comprising a movable element which is movable between a firstposition and a second position. The movable element comprises an orifice40 therethrough. The liquid flows through the orifice 40 to the outlet115 when the movable element is in the first position. The liquid doesnot flow through the orifice 40 to the outlet 115 when the movableelement is in the second position.

FIG. 3 schematically illustrates an example device 5 implanted in theeye in accordance with certain embodiments described herein. The device5 of FIG. 3 is placed upon the conjunctiva of the eye and cannula 110 isinserted through to the posterior chamber of the eye. As described morefully below, the reservoir 100 of certain embodiments includes aneedle-pierceable portion of a first wall 10 that serves as a fill portfor the reservoir 100. The device 5 administers fluid to the posteriorchamber through the cannula 110 and the valve 120, which in thisembodiment is located at or near the end 117 of the cannula 110 insertedinto the posterior chamber. In certain other embodiments, the device 5can be used to administer fluid to the anterior chamber of the eye,which is separated front the posterior chamber by the lens. In certainother embodiments, the device 5 is implanted in other portions of thebody (e.g., in the sub-arachnoid space of the brain for providingchemotherapy or in a pancreas that does not respond well to glucose nextto beta cells to provide materials (e.g., proteins, viral vectors) thatwill trigger insulin release. In certain embodiments, the device 5 isadvantageously refutable. In certain such embodiments, the reservoir 100comprises a first wall 10 which is generally puncturable by a needle(not shown), thereby allowing refilling of the reservoir 100 through theneedle. At least a portion of the first wall 10 of certain embodimentscomprises a soft plastic material that can be punctured with a needleand which reseats itself upon removal of the needle, thereby providing aself-sealing portion of the first wall 10. The self-sealing materialadvantageously provides a reservoir refill site that can withstandmultiple punctures, and is biocompatible. Examples of such materialscompatible with certain embodiments described herein include, but arenot limited to, polydimethylsiloxane (PDMS), polycarbonates,polyolefins, polyurethanes, copolymers of acrylonitrile, copolymers ofpolyvinyl chloride, polyamides, polysulphones, polystyrenes, polyvinylfluorides, polyvinyl alcohols, polyvinyl esters, polyvinyl butyrate,polyvinyl acetate, polyvinylidene chlorides, polyvinylidene fluorides,polyimides, polyisoprene, polyisobutylene, polybutadiene, polyethylene,polyethers, polytetrafluoroethylene, polychloroethers,polymethylmethacrylate, polybutylmethacrylate, polyvinyl acetate,nylons, cellulose, gelatin, silicone rubbers and porous rubbers.

FIG. 4 is a series of photomicrographs which illustrate the stability ofpolydimethylsiloxane (PDMS) as a material for the first wall 10. Threedifferent needle styles were inserted into a slab of PDMS: (i) a20-gauge non-coring needle, (ii) a 30-gauge non-coring needle, and (iii)a 30-gauge coring needle, and the puncture sites were observed usingscanning electron microscopy and optical microscopy. A standardsharp-tipped 20-gauge needle and a 30-gauge non-coring needle allowedthe PDMS to self-seal the puncture hole after the needle was removed.However, the 30-gauge coring needle left a channel in the PDMS after itwas removed. The puncture mechanism in small diameter needles of eitherstandard or non-coring styles appears to tear and displace the PDMSmaterial rather than removing material, thereby allowing the PDMS toreseal the puncture hole. The structural integrity of the PDMS wasobserved after multiple punctures with a 25-gauge needle. Table 1 showsthe relationship between the wall thickness and leakage for testsperformed under atmospheric conditions with leakage determined throughvisual inspection.

TABLE 1 Thickness Number of punctures (millimeters) until failure 0.35571 0.508 7 0.4826 10 0.4578 22 0.5334 21

The refillable reservoir 100 of certain embodiments can be used with avariety of drug-containing fluids. In some cases, it may be desirable toremove any remaining fluid from the reservoir 100 before refilling, forexample to purge the device 5. In certain such embodiments, the fluidcan be changed by removing any remaining fluid from the reservoir byinserting a needle or syringe through the self-sealing portion of thefirst wall 10 and filling the reservoir 100 with a new drug-containingfluid via a needle or syringe inserted through the self-sealing portionof the first wall 10. Purging, if desired, can be effected throughcycles of injection and removal of a purging fluid.

In certain embodiments, refilliability of the reservoir 100advantageously allows the device 5 to be smaller than it may otherwisebe because the reservoir 100 does not have to be sufficiently large tohold a lifetime supply of the drug to be administered. Furthermore, thesmaller size of the device 5 advantageously reduces the invasiveness ofthe device 5 both for implantation and daily use.

In certain embodiments, the refillability of the reservoir 100advantageously allows the physician to tailor the therapeutic regimen tothe patient's changing needs or to take advantages of new advances inmedicine. In certain embodiments, the refillable reservoir 100advantageously stores at least a one-month supply of the drug (e.g., asix-month supply) to reduce the number of refills required.

In certain embodiments, the refillable reservoir 100 comprises amulti-layered structure comprising a first wall 10 and a second wall 50which is generally unpuncturable by the needle. For example, the firstwall 10 of certain embodiments comprises a pliable, drug-impermeablepolymer (e.g., silicone) layer that does not leak after being pierced bya needle, and the second wall 50 comprises a layer comprising lesspliable, more mechanically robust material (e.g., a stiffer materialsuch as a polymer or composite) or comprising a greater thickness of thesame material used to fabricate the first wall 10. In certainembodiments in which the device 5 is implanted in or on the eye, thesecond wall 50 is placed adjacent to the sclera of the eye, and thegreater mechanical strength of the second wall 50 advantageously limitsthe stroke of the needle used to puncture the first wall 10 to refillthe reservoir 100, thereby protecting the eye from accidental punctures.In certain embodiments, the reservoir 100 is formed by bonding the firstwall 10 and the second wall 50 either to each other or to one or moreintervening layers, as described more fully below. In certainembodiments, the reservoir 100 includes integral mechanical supportstructures 60 which reduce the possible contact area between the firstwall 10 and the second wall 50 and which prevent the reservoir 100 fromcollapsing completely. For example, the mechanical support structures 60can comprise one or more protrusions (e.g., posts) extending from atleast one of the first wall 10 and the second wall 50. Other mechanicalsupport structures are also compatible with various embodimentsdescribed herein.

In certain embodiments, the cannula 110 comprises an elongate firstportion 70 and a wall 30 defining a lumen 72 through the cannula 110. Incertain embodiments, the cannula 110 includes one or more integralmechanical, support structures 74 in the lumen 72 of the cannula 110 toprevent fee cannula 110 from collapsing and occluding the lumen 72. Forexample, the mechanical support structures 74 can comprise one or moreprotrusions (e.g. posts) extending from an inner surface of the firstportion 70 of the cannula 110 towards the wall 30 of the cannula 110.Mechanical support structures 74 of certain embodiments have a heightwhich extends from the inner surface of the first portion 70 to the wall30 and a width which extends less than the full width of the lumen 72.Other mechanical support structures are also compatible with variousembodiments described herein.

In certain embodiments, the cannula 110 comprises an end 117 which isconfigured to be inserted into the patient and which comprises theoutlet 115. In certain embodiments, the end 117 of the cannula 110 istapered, to facilitate insertion into the eye. In certain otherembodiments, the end 117 has rounded corners which advantageously alloweasier insertion into the eye. The outer diameter of the cannula 110 ofcertain embodiments is less than or equal to the outer diameter of a25-gauge needle. The outer diameter of the cannula 110 of certain otherembodiments is less than 1 millimeter (e.g., 0.5 millimeter). In certainembodiments in which the device 5 is implantable in or on the eye, theouter diameter of the cannula 110 is sufficiently small to obviate theneed for sutures at the insertion site and thereby to help maintain theintegrity of the eye.

In certain embodiments, the cannula 110 comprises one or more flowregulator structures (e.g., valves) which advantageously maintain aconstant flow rate such that the administered dosage depends on theduration that fluid flows through the cannula 110, rather than on themagnitude of an applied pressure which drives fluid flow through thecannula 110. Certain such embodiments advantageously provide moreaccurate control of the administered dosage. In certain embodiments,instead of, or in addition to, the one or more now regulator structuresof the cannula 110, the reservoir 100 includes one or more such flowregulator structures.

In certain embodiments, the cannula 110 includes one or more fluid flowisolation structures (e.g., valves) which advantageously isolate thereservoir 100 from the body (e.g., the eye) during various operationsinvolving the reservoir 100 (e.g., purging, cleaning, refilling).Certain such embodiments advantageously prevent exchange of fluid (ineither direction) between the reservoir 100 and the patient's body. Incertain embodiments, instead of, or in addition to the one or more fluidflow isolation structures of the cannula 110, the reservoir 100 includesone or more such fluid flow isolation structures.

In certain embodiments, the valve 120 is positioned at or near the end117 of the cannula 110 which is insertable into the patient andcomprises the outlet 115. The valve 120 in certain embodimentsadvantageously prevents unwanted diffusion of the drug from the device 5into the patient's body (e.g., the eye). In certain embodiments, thevalve 120 at or near the end 117 of the cannula 110 advantageouslyprevents backflow of material from, the patient's body into the cannula110.

FIG. 5 schematically illustrates a cross-sectional view of an examplevalve 120 in accordance with certain embodiments described herein. Thecross-sectional view of FIG. 5 is in the plane indicated by the dashedline of FIG. 2. FIG. 6A and FIG. 6B schematically illustratecross-sectional views of an example valve 120 in the first and secondpositions in accordance with certain embodiments described herein. Thevalve 120 comprises a valve seat 80 and a movable element 122 having anorifice 40 therethrough. The movable element 122 of certain embodimentscomprises a flexible portion of a wall 30 of the cannula 110. Theportion of the wall 30 is movable between a first position (asschematically illustrated by FIG. 6B) in which the portion of the wall30 does not contact the valve seat 80, and a second position (asschematically illustrated by FIG. 6A) in which the portion of the wallcontacts the valve seat 80 such that the orifice 40 is occluded. Liquidcan flow through the orifice 40 when the portion of the wall 30 is inthe first position, but does not flow through the orifice 40 when theportion of the wall 30 is in the second position.

The valve seat 80 of certain embodiments comprises a protrusion (e.g.,post) extending from an inner surface of the cannula 110 towards themovable element 122 (e.g., the flexible portion of the wall 30), asshown schematically by FIGS. 5, 6A, and 6B. In certain embodiments, theprotrusion is substantially identical to the one or more integralmechanical support structures in the cannula 110 described above.

In certain embodiments, the portion of the wall 30 moves from the secondposition to the first position in response to pressure applied to theportion of the wall 30 by fluid within the cannula 110, as schematicallyillustrated by FIG. 6A and FIG. 6B. For example, manual pressure appliedto one or more walls of the reservoir 100 can force fluid through thecannula 110 such that the fluid pressure opens the valve 120. In certainembodiments, the valve 120 opens only when the fluid pressure in thecannula 110 exceeds a predetermined threshold value greater than thefluid pressure outside the cannula 110. The valve 120 of certainembodiments advantageously remains closed when the fluid pressure in thecannula 110 is equal to or less than the fluid pressure outside thecannula 110 to prevent biological fluids from flowing backwards into thedevice 5.

FIG. 7 shows a photomicrograph of an example embodiment of the valve 120of an assembled device 5 located at or near the end 117 of the cannula110, FIG. 8 is a series of micrographs showing the delivery of a dyeliquid from a device 5 compatible with certain embodiments describedherein. FIG. 9 is a micrograph showing a device 5 having one or moresuture tabs for affixing the device 5 to the implantation site (e.g.,the eye).

FIG. 10 schematically illustrates another example device 200 inaccordance with certain embodiments described herein. The device 200comprises a reservoir 300 configured to contain a liquid comprising atherapeutic agent. The device 200 further comprises a cannula 310 influid communication with the reservoir 300. The cannula 310 has anoutlet 315 configured to be in fluid communication with the patient. Thedevice 200 further comprises a first electrode 320 and a secondelectrode 330. At least one of the first electrode 320 and the secondelectrode 330 is planar. The device 200 further comprises a material 340in electrical communication with the first and second electrodes 320,330. A voltage applied between the first electrode 320 and the secondelectrode 330 produces gas from the material 340. The gas forces theliquid to flow from the reservoir 300 to the outlet 315. In certainembodiments, the first and second electrodes 320, 330 serve as anelectrolytic pump to drive liquid from the reservoir 300 through thecannula 315 to the outlet 315.

Electrolytic pumps use electrochemically-generated gases to generatepressure that dispense fluid (e.g., drug-containing liquid) from onelocation to another. For example, application of a suitable voltageacross two electrodes (typically gold, palladium, or platinum) immersedin an aqueous electrolyte produces oxygen and hydrogen gases that can beused to apply pressure to a piston, membrane, or other transducer.Electrolysis of water occurs rapidly and reversibly in the presence of acatalyst such as platinum, which in the absence of an applied voltagecatalyzes recombination of the hydrogen and oxygen to reform water. Incertain embodiments described herein, the device useselectrolytically-generated gas to pump the drug from the reservoirthrough the cannula to the patient. In certain such embodiments, use ofelectrolytic pumping advantageously facilitates electronic control overdrag delivery.

Electrolytic pumps offer several advantages for drug delivery. Theirlow-temperature, low-voltage and low-power operation suits them well forlong-term operation in vivo. For ocular applications, electrolytic pumpsadvantageously produce negligible heat, and can also achieve highstress-strain relationships. Moreover, they lend themselves readily touse of microelectronics to control the voltage applied to the pump (andtherefore the temporal pattern of pressure generation), which allowsdevice operation in either bolus and/or continuous dosage mode.Radiofrequency transmission/reception may also be used to providewireless power and control of the microelectronic circuitry to operatethe pump.

Electrolysis in a chamber in fluid communication with its exteriorgenerates gases that force working fluid out of the chamber. Reversingthe polarity of the applied voltage can reverse the process, therebyrestoring the chamber to its original state. Since a small tricklecharge can prevent this reverse process, this device can be held inplace with little power (i.e., the device is latchable).

FIG. 11 is a view of a first portion 350 of an example device 200 inaccordance with certain embodiments described herein. The first portion350 includes the cannula 310, the first electrode 320, and the secondelectrode 330 of an example device 200 in accordance with certainembodiments described herein. For the device 200 of FIG. 11, thematerial 340 also comprises the drug to be administered to the patient.In certain embodiments, the cannula 310 comprises parylene and is influid communication with the reservoir 300 through a pump outlet 317.The first electrode 320 and the second electrode 330 of FIG. 11 areinterdigitated with one another. Such a configuration can advantageouslyensure that the material 340 is in electrical communication with boththe first electrode 320 and the second electrode 330.

FIGS. 12A and 12B are photographs of the first portion 250 of the device200 and a second portion 260 of the device 200. The second portion 260is mountable onto the first portion 250, thereby forming a reservoir 300therebetween, with the first electrode 320 and the second electrode 330inside the reservoir 300. The second portion 260 of certain embodimentscomprises a liquid- and gas-impermeable material (e.g., silicone) whichis self-sealing to repeated punctures, as described above.

FIGS. 13A and 13B schematically illustrate a top- and aside-cross-sectional view, respectively, of a first portion 250 ofanother example device 200 which utilizes electrolytic pumping inaccordance with certain embodiments described herein. The first portion250 comprises a support layer 305, a first electrode 320, and a secondelectrode 330. The first and second electrodes 320, 330 are over thesupport layer 305, and at least one of the first electrode 320 and thesecond electrode 330 is planar.

The support layer 305 of certain embodiments is liquid- andgas-impermeable, and in certain such embodiments, is also electricallyinsulative such that, absent any conductive material above the supportlayer 305, the first electrode 320 and the second electrode 330 areelectrically insulated from one another. The first electrode 320 and thesecond electrode 330 are configured to be in electrical communicationwith a voltage source (not shown) which applies a voltage differenceacross the first electrode 320 and the second electrode 330.

As schematically illustrated in FIGS. 13A and 13B, in certainembodiments, both the first and second electrodes 320, 330 are planarand are co-planar with one another. In certain embodiments, at least oneof the first electrode 320 and the second electrode 330 is patterned tohave elongations or fingers within the plane defined by the electrode.For example, as schematically illustrated by FIG. 13A, the firstelectrode 320 is elongate and extends along a generally circularperimeter with radial elongations 322 which extend towards the center ofthe generally circular perimeter of the first electrode 320. The secondelectrode 330 of certain embodiments has a center elongate portion 332with generally perpendicular elongations 334 extending therefrom. Incertain embodiments, the elongations 334 define a generally circularperimeter within the generally circular perimeter of the first electrode320, as schematically illustrated by FIG. 13A. Other shapes andconfigurations of the first electrode 320 and the second electrode 330are also compatible with certain embodiments described herein.

The first portion 250 of certain embodiments further comprises an outerwall 360 which is liquid- and gas-impermeable. As described more fullybelow, the outer wall 360 is configured to be bonded to a correspondingwall of the second portion 260 of the device 200.

The first portion 250 of certain embodiments further comprises a firststructure 370 between the first electrode 320 and the second electrode330. As schematically illustrated in FIG. 13A, in certain embodiments,the first structure 370 comprises a generally circular wall extendinggenerally perpendicularly from the support layer 305. The firststructure 370 of certain embodiments has one or more fluid passageways372 through which a liquid can flow between a first region 380 above thefirst electrode 320 and a second region 385 above the second electrode330, as described more fully below. In certain embodiments, the firststructure 370 comprises a liquid-permeable but gas-impermeable barrierbetween the first and second regions 380, 385.

In certain embodiments, the first portion 250 further comprises a secondstructure 374 above the first electrode 320 and a third structure 376above the second electrode 330. In certain embodiments, the secondstructure 374 is mechanically coupled to the first structure 370 and theouter wall 360, as schematically illustrated by FIG. 13B, such that thesupport layer 305, the outer wall 360, the first structure 370, and thesecond structure 374 define a first region 380 containing the firstelectrode 320. In certain embodiments, the third structure 376 ismechanically coupled to the first structure 370, as schematicallyillustrated by FIG. 13B, such that the support layer 305, the firststructure 370, and the third structure 376 define a second region 385containing the second electrode 330.

In certain embodiments, at least one of the second structure 374 and thethird structure 376 is flexible and is liquid- and gas-impermeable. Forexample, at least one of the second structure 374 and the thirdstructure 376 comprise a flexible membrane (e.g., corrugated parylenefilm). At least one of the second structure 374 and the third structure376 is configured to expand and contract with increases and decreases inpressure in the corresponding first region 380 and/or second region 385.In certain such embodiments, both the second structure 372 and the thirdstructure 374 comprise portions of the same flexible membrane, asschematically illustrated by FIG. 13B.

In certain embodiments, a pair of interdigitated electrodes isfabricated on the same substrate as a parylene cannula for directingdrugs. The electrolysis reaction can either occur in the same chambercontaining the drug to be delivered or in a separate electrolysischamber adjacent to the drug reservoir. In the latter case, the workingfluid, or electrolyte, is sealed inside the electrolysis chamber.

FIGS. 14A and 14B schematically illustrate a top view and aside-cross-sectional view of an example device 200 comprising the firstportion 350 and a second portion 260 in accordance with certainembodiments described herein. The second portion 260 of certainembodiments comprises a liquid-impermeable wall which is configured tobe bonded to corresponding portions of the first portion 250 of thedevice 200. As schematically illustrated by FIGS. 14A and 14B, thesecond portion 260 of certain embodiments is bonded to the outer wall360 of the first portion 250 such that the second portion 260, thesecond structure 374, and the third, structure 376 define a reservoir390 configured to contain a drug.

The device 200 of certain embodiments further comprises a cannula 110with one or more outlets 115. The cannula 110 is configured to bepositioned such that the one or more outlets 115 are in fluidcommunication with the patient's body (e.g., the eye). In certainembodiments, the cannula 110 comprises parylene and has a generallyelongate shape with a lumen therethrough in fluid, communication withthe reservoir 390 and the one or more outlets 115, as schematicallyillustrated by FIG. 14B.

In certain embodiments, the first region 380 and the second, region 385contain a material 390 which emits gas when a sufficient voltage isapplied to the material 390. For example, in certain embodiments, thematerial 390 comprises water which is electrolytically separated by anapplied voltage into hydrogen gas and oxygen gas. As schematicallyillustrated by FIG. 14B, in certain embodiments, both the secondstructure 374 and the third structure 376 comprise liquid- andgas-impermeable flexible membranes, and gas generated at the firstelectrode 320 increases the pressure in the first region 380, therebyflexing the second structure 374 towards the reservoir 390. Furthermore,gas generated at the second electrode 330 increases the pressure in thesecond region 385, thereby flexing the third structure 376 towards thereservoir 390. The flexing of at least one of the second structure 374and the third structure 376 forces liquid (e.g., containing atherapeutic agent) to flow from the reservoir 390, through the cannula110, to the one or more outlets 115.

In certain embodiments, the device 200 advantageously restricts gasproduced at the first electrode 320 from mixing with gas produced at thesecond electrode 330. For example, as schematically illustrated by FIG.14B, when the material 390 comprises water, hydrogen gas produced at oneelectrode (e.g., the first electrode 320) is generally restricted to thefirst region 380 and gas produces at the other electrode (e.g. thesecond electrode 330) is generally restricted to the second region 385.Gas generated at either or both of first and second electrodes 320 and330 increases the volume of either or both of first chamber 300 orsecond chamber 330, expanding electrolytic chamber membrane 360 andthereby forcing liquid to flow from reservoir 300 through cannula 110.

FIGS. 15A-15D schematically illustrate various views of the exampledevice 200 of FIGS. 14A and 14B. FIG. 15A schematically illustrates atop view of the device 200 with the first electrode 320, the secondelectrode 330, the second portion 260, and the cannula 110. FIG. 15Bschematically illustrates a top-partially cut-away view that shows thefirst electrode 320, the second electrode 330, the second portion 260,the cannula 110, and the second structure 374 and the third structure376. As shown in FIG. 15B, the second structure 374 and the thirdstructure 376 are portions of a membrane extending across the firstportion 250 of the device 200. FIG. 15C schematically illustrates afurther top-partially cut-away view that shows a portion of the firstregion 380, the first electrode 320 in the first region 380, the secondregion 385, the second electrode 330 within the second region 385, thefirst structure 370, and the outer wall 360, as well as the secondportion 260 and the cannula 110. FIG. 15D schematically illustrates aside cross-sectional view of the device 200 which does not containeither the material 390 or the drug, and which corresponds to the filleddevice 200 schematically illustrated by FIG. 14B.

FIG. 16 schematically illustrates various views of an example device 200comprising an injection port 410 configured to receive an injectionneedle 420. The injection port 410 of certain embodiments is part of thefirst portion 250 of the device 200, while in certain other embodiments,the injection port 410 is part of the second portion 260 of the device250. The injection port 410 is in fluid communication with the reservoirof the device 200 to facilitate refilling of the device 200 while thedevice 200 is implanted, in addition, the device 200 schematicallyillustrated by FIG. 16 includes suture tabs 400 for fastening the device200 to the patient's body (e.g., the surface of the eye).

FIG. 17 schematically illustrates the internal structure of an exampleinjection port 410 compatible with certain embodiments described herein.Injection needle 420 pierces injection port surface 500 through needleinjection guide 510, and thereby gains access to injection vestibule520. Injection of fluid, into the vestibule 520 forces liquid throughthe injection port valve 530 and into the reservoir 540.

In certain embodiments, the device 200 is powered by an internal battery(not shown), while in certain other embodiments, the device 200 ispowered by an external source (not shown). In certain embodiments, botha battery and an external source are used. For example, even though thepower can be recharged wirelessly, a smaller battery may be used tostore the power for a week, thereby advantageously keeping the devicesmall and minimally invasive.

The external source can be electrically coupled to the device 200 usingwires or by wireless means (e.g., radiofrequency transmitter/receiver).By utilizing an external source and avoiding the use of an internalbattery, the device 200 can advantageously be made smaller, andtherefore less invasive. In addition, by wirelessly controlling theoperation of the device 200 (e.g., turning it on and off), a handheldtransmitter can be programmed to send a signal that communicates withthe device to power the device when needed. For example, at times whenless drug is needed, less power is transmitted, and less drug is pumped.There will, be some threshold cutoff on the external power applicatorfor example that limits the implant from pumping too much drug. Wirelesspower is through the use of coils built into the implant and theexternal transmitter through a process of inductive powering.

In certain embodiments, the device 200 includes an integrated circuitfor controlling operation of the device 200. Examples of integratedcircuits compatible with certain such embodiments include but are notlimited to, single-chip application-specific integrated circuits (ASICs)and application-specific standard products (ASSPs) that have become morecommon for implantable medical applications. Certain such integratedcircuits advantageously consume as little power as possible, e.g., toextend battery life, and therefore lengthen the time between invasivereplacement procedures. The ASIC will be the predominant chip for thisimplant that will help add additional features in its current low powerembodiment. In certain embodiments, the device can includemicroelectronics to control the dosage and release, sensors for feedbackcontrol, anchoring structures to hold, the device in place, supports tokeep the reservoir from collapsing on itself when emptied, filteringstructures, additional valves for more accurate flow control, a flowregulator to remove the adverse effects of pressure on drug delivery,and a programmable telemetry interface.

In certain embodiments, the device comprises a plurality of structurallayers which are bonded together to form a reservoir configured tocontain a liquid and a cannula in fluid communication with thereservoir. The cannula has an outlet configured to be in fluidcommunication with the patient. For example, the device can comprisethree individual layers of a biocompatible polymer, such aspolydimethylsiloxane, that are fabricated separately and then bondedtogether, as schematically illustrated by FIGS. 1 and 2. In this examplestructure, the lower layer forms the base of the device outlining thereservoir, the cannula, and the valve. This lower layer contains poststhat mechanically support the cannula and the reservoir to prevent itfrom collapsing and that provide the valve seat for the valve, asdescribed more fully above. The middle layer forms the cannula and themovable portion of the valve. The upper layer forms the upper half ofthe reservoir.

In certain such embodiments, at least one of the structural layers isformed rising a lithographic process (e.g., soft lithography). FIGS.18A-18K schematically illustrates an example lithographic process inaccordance with certain embodiments described herein. As schematicallyillustrated by FIG. 18A, a substrate (e.g., silicon wafer) is provided.As schematically illustrated by FIG. 18B, a photoresist layer is formedon the substrate (e.g., by spin-coating a light-sensitive liquid ontothe substrate). Suitable photoresists are well-known to those skilled inthe art, and include, but are not limited to, diazonaphthoquinone,phenol formaldehyde resin, and various epoxy-based polymers, such as thepolymer known as SU-8. As schematically illustrated by FIG. 18C, thephotoresist layer is patterned to cover a first portion of the substrateand to not cover a second portion of the substrate. For example,ultraviolet light can be shone through a mask onto thephotoresist-coated wafer, thereby transferring the mask pattern to thephotoresist layer. Treatment of the water by well-known photoresistdevelopment techniques can be used to remove the portions of thephotoresist layer that were exposed to the ultraviolet light. Personsskilled in the art of lithographic techniques are able to selectappropriate materials and process steps for forming the patternedphotoresist layer in accordance with certain embodiments describedherein.

As schematically illustrated by FIG. 18D, the portion of the substratethat is not covered by the patterned photoresist layer is etched (e.g.,by deep reactive-ion etching), thereby leaving untouched the portions ofthe silicon wafer protected by the photoresist layer. As schematicallyillustrated by FIG. 18E, the patterned photoresist layer is removed. Forexample, after washing with a solvent, such as acetone, the photoresistlayer is removed and the entire wafer can be cleaned through use ofoxygen plasma to remove any remaining photoresist. As schematicallyillustrated by FIG. 18F, a mold release layer (e.g., parylene, awidely-used polymer of p-xylene) is formed on the substrate tofacilitate removal of the PDMS layer from the silicon wafer. Othermaterials can be used as the mold release layer in other embodiments. Asschematically illustrated by FIG. 18G, the structural layer (e.g., PDMSsilicone) is formed on the mold release layer. For example, PDMS can bepoured over the silicon water and allowed to cure either by standing atroom temperature or accelerated, by heating (e.g., to 75° C. for 45minutes). As schematically illustrated by FIG. 18H, the structural layeris removed from the substrate, thereby providing the structural layerschematically illustrated by FIG. 18I. In certain embodiments, themolded PDMS layer contains multiple copies of the structural layer, andeach copy of the structural layer is separated from the others. Excessmaterial can be removed from the structural layer, as schematicallyillustrated by FIG. 18I, thereby providing the structural layerschematically illustrated by FIG. 18K, ready for assembly with the otherstructural layers.

The individual structural layers can be assembled and bonded together incertain embodiments by treating the surface of one or more of thestructural layers with oxygen plasma for about one minute, although thetime is not critical. Oxygen plasma changes the surface of thepolydimethylsiloxane from hydrophobic to hydrophilic.

In certain embodiments, the bottom layer and the middle layer are placedinto a plasma chamber with the sides that are to be bonded facing theplasma. Once the surfaces have been treated, the two pieces can bealigned with the aid of any polar liquid (e.g., ethanol, water). Theliquid preserves the reactive hydrophilic surface providing more time toalign the two layers. It also makes the pieces easier to manipulate foralignment since it lubricates the surfaces, which are otherwise sticky.The two-layer assembly can then be placed back into the chamber alongwith the top layer and the treatment and alignment procedure repeated.The entire assembly can then be baked (at 100° C. for 45 minutes) toreinforce the bonds. The bonded silicone appeared homogeneous by SEM andoptical observation. Tests with pressurized N₂ showed that the bondedsilicone assembly withstood pressures of at least 25 psi.

In certain embodiments, the orifice 40 is made by, for example,inserting a small diameter coring needle into a sheet of silicone rubberthat later forms the upper surface of the cannula. Other methods canalso be used to generate this feature. The coring needle removesmaterial to create the orifice. The valve seat 80 of certain embodimentsis a post that protrudes from the bottom of the cannula 110 and extendsthe height of the channel to meet the top of the cannula. Duringassembly, the orifice 40 is centered over the valve seat 80 and rests onit to form the valve. In this configuration, the valve is said to be“normally-closed” and fluid will not pass through. Fluid, pressure inthe cannula 110 exceeding a certain value (cracking pressure) opens thevalve and allows fluid to exit the device through a gap between valveseat 80 and movable element 122, as schematically illustrated by FIGS.6A and 6B.

FIGS. 19A-19M schematically illustrate an example process for forming adevice that includes electrolytic pumping. While FIGS. 19A-19Mschematically illustrate example processes for forming a deviceutilizing electrolytic pumping, other methods can be used in accordancewith certain embodiments described herein.

As schematically illustrated by FIG. 19A, a bare silicon substrate isprovided and as schematically illustrated by FIG. 19B, a dielectriclayer (e.g., a thermal silicon dioxide layer about 4000 Å thick) isgrown on the silicon substrate. This silicon oxide layer electricallyinsulates the substrate and electrolysis electrodes.

Electrolysis electrodes (e.g., made of Ti/Pt, 200 Å/2000 Å thick,respectively) are formed over the dielectric layer (e.g., deposited andlithographically patterned), as schematically illustrated by FIG. 19C.The dielectric layer is patterned and etched briefly with XeF₂ to removea portion of the dielectric layer, thereby exposing a portion of thesubstrate. This process can also roughen the exposed silicon surface, asschematically illustrated by FIG. 19D. A first sacrificial photoresistlayer (e.g., 5 μm thick) can be span and patterned on the substrate, asschematically illustrated by FIG. 19E. The first sacrificial photoresistlayer facilitates the release of the cannula from the supporting siliconsubstrate at the end of the fabrication process. A first structurallayer (e.g., 7.5 μm thick parylene layer) can be deposited and patternedon the first sacrificial layer, as schematically illustrated by FIG.19F, which will become the bottom wall of the drag delivery cannula. Asschematically illustrated by FIG. 19G, a second sacrificial layer (e.g.,25 μm thick photoresist layer, spun and patterned) can be formed overthe first structural layer. As schematically illustrated by FIG. 19H, asecond structural layer (e.g., 7.5 μm thick parylene) can be depositedon the second sacrificial layer, and which will become the top and sidewalls of the cannula. The first and second structural layers can then bepatterned, as schematically illustrated by FIGS. 19I and 19J. Forexample, a Cr/Au etch mask layer for removing unwanted parylene (200Å/2000 Å thick, respectively) can be deposited and patterned on thesubstrate, as schematically illustrated by FIG. 19I. The parylene can bepatterned in an oxygen plasma through use of the Cr/Au masking layer, asschematically illustrated by FIG. 19J. A third structural layer (e.g.,an SU-8 photoresist layer 70 μm thick) can be spun and patterned on thesubstrate, as schematically illustrated by FIG. 19K. The SU-8 layersupports the cannula and prevents its collapse when a drag reservoir isattached to the base layer. The sacrificial photoresist layers are thenremoved by dissolving them in acetone, as schematically illustrated byFIG. 19L. The cannula can be peeled up from the surface of the roughenedsilicon substrate and broken off the silicon substrate directly beneaththe cannula to form a free-standing cannula, as schematicallyillustrated by FIG. 19M.

In certain embodiments, the device is implanted by attaching the mainbody of the device to the top of the eye and inserting the cannula intothe anterior or the posterior segment of the eye. The device is affixedto the eye through use of current ophthalmic techniques such as suturesor eye tacks, in certain embodiments, a method of using the devicecomprises applying a first voltage between the first electrode and thesecond electrode to produce gas from the material in electricalcommunication with the first and second electrodes. The gas forcesliquid from the reservoir to flow from the reservoir to the outlet ofthe device. In certain embodiments, the method further comprisesapplying a second voltage between the first electrode and the secondelectrode to produce the material from the gas. In this way, the deviceis used in a reversible manner in which the material can be regeneratedfrom the gases, thereby avoiding having to refill the device with thematerial. In certain embodiments the material comprises water and thegas comprises hydrogen gas and oxygen gas. In certain embodiments, thefirst voltage and the second voltage are opposite in sign.

Example

A device having a flexible parylene transscleral cannula allowingtargeted delivery to tissues in both the anterior and posterior segmentsof the eye is described below. The electrochemically driven drugdelivery device was demonstrated to provide flow rates suitable forocular drug therapy (pL/min to μL/min). Both continuous and bolus drugdelivery modes were performed to achieve accurate delivery of a targetvolume of 250 nL. An encapsulation packaging technique was developed foracute surgical studies and preliminary ex vivo drug delivery experimentsin porcine eyes were performed.

Pharmaceuticals for eye treatment advantageously penetrate theprotective physiological barriers of the eye such as the cornea, sclera,and the blood-retina barrier and to target difficult-to-reachintraocular tissues such as the ciliary body, retina, and angle.

With miniaturized MEMS devices, precise delivery in either bolus orcontinuous mode is possible. The advantages of MEMS fabrication forproducing miniaturized and efficient drug delivery systems are capableof targeted delivery to an interior tissues, refutable for long-termuse, and automated to address patient compliance.

The electrolysis of water results in the phase transformation of liquidto gas and provides the actuation used to drive drug deliver in thisexample device. The net result of the electrolysis is the production ofoxygen and hydrogen gas that contributes to a volume expansion of abouta thousand times greater than that of the water used in the reaction.This gas evolution process proceeds even in a pressurized environment(e.g., 200 MPa). To drive gas generation and thus pumping, currentcontrol is useful for its direct correlation to pump rate and volume. Ifcurrent is used to drive the reaction, the theoretical pump rate(q_(theoretical) in m³/s) at atmospheric pressure is given by:q_(theoretical)=0.75 (I/F)V_(m), where I is current in amperes, F isFaraday's constant and V_(m) is the molar gas volume at 25 degreesCelsius and atmospheric pressure. The theoretical generated or dosed gasvolume (V_(theoretical) in m³) can be determined by:V_(theoretical)=q_(theoretical)t, where t is the duration (in sec) thatthe current is applied. The efficiency (η) of an electrolysis actuatoras a pump can be defined, as: η=V_(experimental)/V_(theoretical), whereV_(experimental) is the actual volume of the generated hydrogen andoxygen gases. Efficiency in electrochemical systems is affected by anumber of parameters including electrode (material, surface area,geometry, and surface conditions), mass transfer (transport mode,surface concentration, adsorption), external (temperature, pressure, andtime), solution (Bulk concentration of electroactive species,concentration of other species, solvent), and electrical (potential,current, quantity of electricity).

The electrolysis pump consists of two interdigitated platinum,electrodes immersed in an electrolyte. This electrode geometry improvespumping efficiency by reducing the current path through the solutionwhich serves to lower the heat generation. The gasses generated resultin an internal pressure increase in the sealed reservoir which causesdrug to be delivered through the cannula and into the eye. Electrolysisis a reversible process and ceases when the applied signal is turnedoff, thereby allowing the gradual recombination of hydrogen and oxygento water.

Using the device illustrated by FIGS. 11, 1A, and 12B, pumped drugentered a flexible transscleral cannula through a small, port connectedto the pump while the generated gases remain trapped inside thereservoir. Parylene was selected as the cannula material for itsmechanical strength, biocompatibility, and ease of integration. It is aUSP Class VI material suitable for the construction of implants and iswell-established as a MEMS material. The pump/cannula portion wasfabricated using silicon micromachining and the reservoir portion by thecasting of silicone rubber against a master mold.

The fabrication process of the pump and cannula chip started with athermally oxidized silicon substrate (5000 Angstroms). LOR 3B (MIcroChemCorp., Newton, Mass.) was spun on at 3 krpm followed by AZ 1518 (AZElectronic Materials, Branchburg, N.J.) at 3 krpm. Ti—Pt (200/2000Angstroms was e-beam evaporated and patterned by lift-off in ST-22photoresist stripper (ATMI, Banbury. CT) to define the interdigitatedelectrodes. A second lithography step was performed (AZ 1518 at 3 krpm)to define the cannula footprint. The oxide layer was etched usingbuffered HF acid to expose the Si below. The photoresist was stripped,then the exposed Si was roughened by two cycles of XeF2 etching. Thefirst sacrificial photoresist layer (AZ 4620 spun at 2.75 krpm and hardbaked to yield a 5 micron thick layer) was applied to facilitate releaseof the cannula from the substrate. The first parylene C layer (7.5microns) forming the bottom of the cannula was deposited followed bythermal evaporation of 2000 angstroms thick Cr etch mask. Followinglithography (AZ 4620 at 500 rpm) the CR is etched in CR-7 (Cyanteck,Fremont, Calif.) and the photoresist is tripped. The parylene layer isthen patterned in an oxygen plasma and the Cr etch mask is removed usingCr-7. A second photoresist sacrificial layer was deposited (AZ 4620 spanat 450 rpm and hard baked to yield a 25 micron thick layers to definethe channel height. A second parylene layer of 7.5 microns was depositedto complete the cannula. To define the cannula from theparylene/photoresist/parylene sandwich, Ti/Au (200/2000 angstroms) wasdeposited as an etch mask. The etch mask was pattered (AZ 4620 spun at425 rpm) and etched first with Au etchant TFA (Transene Company, Inc.,Danvers, Mass.) and then 10% HF. Finally, the sandwich is etched inoxygen plasma and the masking layer is stripped (Au etching TFA and 10%HF). Following the etch, the entire wafer was cleaned in 5% HF dip andby exposure to oxygen plasma. SU-8 2200 (MicroChem Corp., Newton, Mass.)was spun at 2200 rpm resulting in a 70 micron thick layer after postbaking. The sacrificial photoresist was removed by dissolving in a 40degree Celsius acetone solution for one day. The individual cannulaswere released manually by gently lifting them of the substrate. Finally,individual dies were separated and the remaining silicon beneath eachcannula was removed by scribing and breaking it off.

The pump chip containing the electrolysis actuator and cannula wascombined with the drug reservoir and electrical wiring. The finalproduct after assembly is shown in FIGS. 12A and 12B. Electrical wireswere bonded to the electrode contact pads using Ohmex-AG conductiveepoxy (Transene Company, Inc., Danvers, Mass.). The epoxy was cured at150 degrees Celsius for 15 hours under vacuum. The pump chip andreservoir were then assembled using an encapsulation technique based onsilicone soft lithography as described above.

To shape the package to fit comfortably on the curved contour of theeyeball, a silicone spacer (Sylgard 184, Dow Corning, Midland, Mich.)was casted against a stainless steel sphere of 17.5 mm in diameter. Thislayer of partially cured, silicone (10:1 base to curing agent ratio,cured at 65 degrees Celsius for 20 minutes. The sphere was removed andthe resulting crater was filled with wax. A silicone reservoir wasprepared by casting against a conventionally machined acrylic mold,partially-cured at 65 degrees Celsius for 20 minutes. The mold producesa reservoir with internal dimensions of 6 mm×6 mm×1.5 mm. The siliconereservoir was aligned to the chip and spacer and the parylene cannula,was then immersed in DI water which serves a mask to prevent coating bysilicone rubber during the encapsulation step, thereby exploiting thehydrophobicity of silicone rubber. The stack was immersed in siliconeprepolymer and cured at room temperature for 24 hours. Extraneoussilicone material was removed from the device to complete the assemblyprocess.

To investigate the performance of the electrolysis pump, experimentsexamining continuous delivery, bolus delivery, pump efficiency, gasrecombination, and backpressure were conducted. For these tests, acustom testing apparatus was laser-machined (Mini/Helix 8000, Epilog,Golden, Colo.) in acrylic. The experimental setup consisted of acomputer-controlled CCD camera (PL-A662, pixeLINK, Ottawa, Canada) forcollecting flow data from a calibrated micro-pipette (Accu-Fill 90,Becton, Dickinson and Company) attached to the output port of the testfixture. Testing was performed using deionized water as the electrolyte.The electrolysis was initiated under constant current conditions (50 μAto 1.25 mA) for continuous delivery operation. The relationship betweenefficiency and recombination of hydrogen and oxygen to water wasstudied.

Bolus delivery was also examined. A constant current pulse (0.5, 1.0,and 1.5 mA) was applied for 1, 2, and 3 seconds. Repeated trials wereperformed (n=4) to obtain average dosing volume. Normal intraocularpressure GOP) ranges from 5-22 mm Kg (15.5±2.6 mmHg (mean±SD)), Valuesoutside this range correspond to abnormal intraocular pressure which isa characteristic of glaucoma (>22 mmHg). Thus, it is helpful tocharacterize pump performance under these physiologically relevantconditions. The experimental setup was modified to include a watercolumn attached to the outlet of the micro-pipette. Backpressure wasapplied to the drug delivery device by adjusting the height of the watercolumn. Data was collected for backpressures corresponding to normal IOP(20 mmHg) and abnormal IOP (0 and 70 mmHg).

The prototype drug delivery devices were implanted in enucleated porcineeyes. Preliminary ex vivo surgical modeling in enucleated porcine eyesis useful to prepare for device demonstration in vivo. The operation ofeach surgical device was tested prior to the surgical experiment tocheck for clogs and integrity of the electrical connections. The drugreservoir was filled with dyed deionized water then the reservoirs weremanually depressed which generates sufficient pressure to expel thefluid from the reservoir. A second, test is conducted to verifyoperation of the electrolysis pump by connecting to an external powersupply and driving fluid from the reservoir by electrolysis pumping. Anenucleated porcine eye was prepared, for the surgical study and a limbalincision was made (between the cornea and sclera). The cannula wasimplanted through the incision into the anterior chamber (FIG. 20). Theenucleated porcine eye was pressurized at 15 mmHg by using an infusionline. Constant current (0.5 mA) was applied for 1 minute. The device wassurgically removed after the experiment.

The electrolysis pump was operated at flow rates in the pL/min to μL/minrange using driving currents from 5 μA to 1.25 mA (FIGS. 21A and 21B).The highest rate was 7 μL/min for 1.25 mA and the lowest was 438 pL/minat 5 μA. Both data sets am corrected to compensate for the evaporationof fluid during testing. Flow rates below about 2 μL/min are preferredfor ocular drug delivery. This is consistent with naturally occurringflow sates in the eye; the ciliary body of the eye produces aqueoushumor at 2.4±0.6 μL/min in adults. As current decreases, it was observedthat pumping efficiency, which ranged from 24-49%, also decreased (FIG.21C) Electrolysis-driven pumping efficiency is affected by thecompetitive recombination of hydrogen and oxygen gases to water. Thiseffect is further enhanced by exposure to the platinum electrolysiselectrodes which serve to catalyze the recombination reaction. In FIG.21D, a typical accumulated volume curve is shown that illustrates theeffect of recombination after the applied current is turned off. Themeasured recombination rate was 62 nL/min.

Bolus delivery mode is also evaluated (FIG. 22). If the desired dosingregimen is 250 nL per dose, this volume can be obtained by driving thepump for a short duration that is determined by the magnitude of theapplied current. For example, a 1.0 mA driving current will dose 250 nLin 2.36 second and, for 1.5 mA current, the pulse time can be set as1.75 second. Under normal operation in the eye, the drug delivery devicewill experience a backpressure equivalent to the IOP of the eye.Benchtop experiments indicated that the pump was able to supplysufficient drug flow over the range of normal and abnormal IOPequivalent backpressures (FIG. 23). The flow rates varied 30% comparedto normal IOP over the tested backpressure range.

Initial surgical results show promising results in enucleated porcineeyes. Following removal of the device after the surgical experiment,post surgical examination of the cornea revealed a small blue spot abovethe iris near the position of the cannula tip indicating that dye wasdelivered into the eye.

The above description is by way of illustration only and is not intendedto be limiting in any respect. While the above detailed description hasdescribed features of the invention as applied to various embodiments,the scope of the invention is indicated by the appended claims ratherthan by the foregoing description.

1.-20. (canceled)
 21. A method of manufacturing an implantable pump, themethod comprising: providing an upper layer comprising a dome structurefor housing a drug chamber and a cannula in fluid communication with thedrug chamber; providing a middle deflection layer adjacent the drugchamber; providing a bottom layer comprising electrolysis electrodes;and bonding the upper layer, middle deflection layer, and bottom layerto form the pump.
 22. The method of claim 21, further comprising thestep of forming the drug chamber between the upper layer and the middledeflection layer after thermal bonding.
 23. The method of claim 21,further comprising the step of forming the electrolysis chamber betweenthe middle deflection layer and the bottom layer after thermal bonding.24. The method of claim 21, further comprising providing at least onefill port in fluid communication with at least one of the electrolysischamber or the drug chamber.
 25. The method of claim 21, wherein atleast one of the upper layer, the middle layer, and the bottom layer isformed by a lithographic process.
 26. The method of claim 25, whereinthe lithographic process comprises the steps of: sequentially layeringlayers of a construction material and a photoresist material; etching atleast one of the construction material and a photoresist material toprovide a required shape, and subjecting the layers to photoresiststripper, thereby removing the photoresist material and leaving theshaped construction material in place.
 27. The method of claim 21,wherein at least one of the upper layer, the middle layer, and thebottom layer is formed by a molding process.
 28. The method of claim 21,wherein at least one of the upper layer, the middle layer, and thebottom layer comprises or consists essentially of parylene.
 29. Themethod of claim 21, wherein the dome structure is manufactured by thesteps of: providing a mold having a domed shape; conformably coating alayer of material on the mold; and after the material has set, peelingthe resulting dome structure from the mold.
 30. The method of claim 21,wherein the cannula is manufactured according to steps comprising:coating a first photoresist layer onto a silicon substrate as asacrificial layer; depositing a first parylene layer onto thephotoresist layer to form a bottom surface of the cannula; creating athrough hole in the first parylene layer; coating a second photoresistlayer over the first parylene layer; depositing a second parylene layeron the second photoresist layer, the second parylene layer forming a topand a side of the cannula; patterning the first and second parylenelayers to form a cannula shape; and removing the first and secondphotoresist layers, thereby leaving the formed cannula.
 31. The methodof claim 30, wherein the patterning step comprises reactive-ion etchingwith a photoresist material used as an etching mask.
 32. The method ofclaim 30, wherein the patterning step comprises patterning the firstparylene layer and second parylene layer in a RIE oxygen plasma using aphotoresist mask.
 33. The method of claim 30, wherein at least one ofthe coating steps comprises spin-coating.
 34. The method of claim 21,further comprising integrating at least one of a check valve, a flowsensor, a pressure sensor, or a chemical sensor into the pump.
 35. Themethod of claim 21, wherein the middle deflection layer comprises acorrugated diaphragm.
 36. The method of claim 35, wherein the corrugateddiaphragm is formed according to steps comprising: coating a firstphotoresist layer onto a silicon substrate; etching the siliconsubstrate using the first photoresist layer as a mask; removing thefirst photoresist layer, thereby leaving a mold formed by the siliconsubstrate; coating a parylene layer on the silicon substrate; and afterthe parylene layer has set, releasing the parylene layer from thesilicon substrate thereby forming the corrugated diaphragm.
 37. Themethod of claim 21, wherein the middle deflection layer comprises abellows structure.
 38. The method of claim 37, wherein the bellowsstructure is formed according to steps comprising: coating a firstphotoresist layer onto a silicon substrate as a sacrificial layer;depositing a first parylene layer onto the first photoresist layer toform a first layer of the bellows structure; coating a secondphotoresist layer over the first parylene layer; opening a bonding areain the second photoresist layer by lithography; depositing a secondparylene layer onto the second photoresist layer to form a second layerof the bellows structure, wherein the second parylene layer bonds to thefirst parylene layer at the bonding area; patterning the first andsecond parylene layers; coating a third photoresist layer onto thesecond parylene layer; depositing a third parylene layer onto the thirdphotoresist layer to form a third layer of the bellows structure;patterning the bellows structure by etching through the second and thirdparylene layers; and removing the photoresist layers by subjection tophotoresist stripper, thereby leaving the parylene bellows structure.39. The method of claim 21, wherein the bottom layer is formed accordingto steps comprising: coating a first photoresist layer onto a siliconsubstrate as a sacrificial layer; depositing a first parylene layer ontothe first photoresist layer to form a first layer of the bottom layer;depositing a metal electrode layer on the first parylene layer;depositing a second parylene layer over the metal electrode layer;etching the second parylene layers to expose at least a portion of theelectrode; and removing the photoresist layers by subjection tophotoresist stripper, thereby leaving the bottom layer.
 40. The methodof claim 39, wherein the metal electrode layer is deposited by E-beamevaporation and patterned by life-off process or etching process. 41.The method of claim 39, wherein the etching step comprises RIE oxygenplasma etching masked by a photoresist mask.
 42. The method of claim 39,further comprising annealing the bottom layer to improve the adhesionbetween the parylene layers and metal electrode layer.
 43. The method ofclaim 39, wherein the metal electrode layer comprises or consistsessentially of platinum.
 44. The method of claim 21, further comprisinga substantially rigid spacer comprising a refill hole.